1. FIELD OF THE INVENTION
The invention is related to a method of treating benign prostate hypertrophy (BPH) and prostate cancer as well as to means of use therefor.
2. DESCRIPTION OF RELATED ART
BPH is a disease conditioned by age and affects approximately 60% of all men older than 60. Pathogenetically, an elevated accumulation of dihydrotestosterone in the prostate tissue is assumed to cause enlargement of the prostate. The accumulation of dihydrotestosterone is thought to be the result of elevated intracellular bonding based on receptor increase. The increase in receptors is stimulated by the elevation of the estrogen levels relative to androgen levels which decrease with age. The urological symptoms consist in an elevated frequency of miction due to elevated residual urine, which bothers the patients especially during the night hours. This is accompanied by a weak flow of urine, a time-delayed start of miction, and repeated infections of the bladder and kidneys.
Surgical elimination of the obstruction due to prostate enlargement is still considered the "gold standard" within the various modalities of treatment. Surgery, however, is not effective for all patients. Open operation or a transurethral resection results in no improvement in approximately 10 to 15% of the patients due to the presence of other causes, e.g. neurogenic bladder, infections. In addition, these invasive methods entail additional risks such as the occurrence of a retrograde ejaculation, diminished libido and urine incontinence. Less invasive methods exist, e.g. balloon dilatation and treatment with hyperthermia or microwaves.
It has been established that an androgen-ablative therapy can yield positive results in the case of BPH; however, it is unclear whether full suppression should be achieved. The standard therapy for testosterone suppression in the case of prostate carcinomas consists in a bilateral orchiectomy. This is not generally acceptable for a benign sickness such as BPH. Another possibility involves influencing the effects of the sexual steroids through the use of LHRH analogues (LHRH=luteinizing hormone-releasing hormone).
After an initial stimulation of the steroid, the use of "superagonists" causes suppression of testosterone at castration levels. The stimulation is due to their mechanism of action. Unfortunately, the use of "superagonists" has the same undesirable side effects associated with surgical castration.
Dyssynergia .alpha.-receptor blockers can be used in the case of a rigid sphincter or bladder sphincter. Alternative drug regimens involve the use of 5-.alpha.-reductase inhibitors such as Finasteride to inhibit the formation of dihydrotestosterone. This regimen has the additional advantage of not negatively influencing the libido or potency.
EP 0.401,653 teaches the use of Naftopidil for therapy of dysuria in BPH (oral daily 10-100 mg). Dysuria is discussed in the background section.
WO publication 91/100731 describes a combination therapy for the prophylaxis or treatment of BPH by the combined administration of 2 or more therapeutic substances. The substances are selected from the group of 5-.alpha.-reductase inhibitors, anti-estrogens, aromatase inhibitors, inhibitors of 17.beta.-hydroxysteroid dehydrogenase activity and, in a few instances, of anti-androgens and/or LHRH agonists/antagonists. The anti-androgens were preferably given 2 to 4 hours before the administration of the LHRH agonist.
WO publication 91/00733 teaches the treatment of androgen-dependent diseases with a new anti-androgen which can also be used in the context of a combination therapy. The treatment includes the steps of inhibiting the testicular hormonal secretion by administering an antagonist of LHRH or an agonist of LHRH along with a pharmaceutically effective amount of an anti-androgen.
WO publication 92/16233 describes the combined use of an inhibitor of 5-.alpha.-reductase and an anti-androgen for the treatment of prostate cancer. The combination of Finasteride with an anti-androgen, e.g. Flutamide, is also taught. The use of a composition of various LHRH agonists and of an anti-androgen for treating BPH is also suggested by U.S. Pat. No. 4,472,382.
WO publication 92/16213 teaches a method of treating BPH by administering an inhibitor of 5-.alpha.-reductase select from 17.beta.-substituted 4-azasteroid, 17.beta.-substituted non-azasteroid, 17.beta.-acetyl-3-carboxy-androst-3,6-diene together with an .alpha..sup.1 adrenergic receptor blocker selected from Terazosin, Doxazosin, Prazosin, Bunazosin, Indoramin, Alfuzosin.
The use of the LHRH antagonist Cetrorelix (SB 75), (see also EP 0299 402), for treating BPH is suggested in "The Prostate" 24:84 92 (1994), (Gonzalez-Barcena et al). Gonzalez-Barcena et al. report desirable clinical results, e.g. a decrease in prostate volume, after the administration of 500 .mu.g Cetrorelix (SB-075) every 12 hours for 4 weeks to BPH patients. Prostate carcinoma patients were also similarly treated for 6 weeks. In all patients, there was initially a lowering in testosterone levels to a castration level. In the BPH patients, the testosterone levels fluctuated at subnormal levels. None of the patients had testosterone levels which reached castration values during the last three weeks of the treatment. There was a distinct decrease of the symptoms of dysuria and also the prostate volume. In the prostate carcinoma patients, the testosterone values were measured again at the castration levels at the end of the 6 weeks of therapy along with a considerable improvement in the overall condition of the patient.
The potential suitability of LHRH antagonists, including Cetrorelix, for treating BPH appears in a review article appearing in Arch.-Pharmakol. 350, Suppl., R16, 1994 (Romeis, Ochs, Borbe). In vitro bonding of Cetrorelix to LHRH receptors on the pituitary gland of swine is mentioned. Also mentioned are other possible clinical areas of application, including hormone-dependent tumors.
A comparative survey of the endocrine therapy of BPH in conjunction with 5-.alpha.-reductase inhibitors, aromatase inhibitors and anti-androgens is presented in Urology, 1994, 43, 22 suppl. (7-16). However, only LHRH agonists are described.
An overriding disadvantage of known preparations and methods is that the patient usually experiences a sharp drop in testosterone levels along with its associated side effects. In addition, known preparations have only a relatively short term effect. The prostate volume rises once administration stops. An effective therapy scheme for the treatment of BPH with Cetrorelix has not been established.